Without the understanding taught by this invention, prior teachings and practice have focused on limited and, at times, iatrogenic treatments for Distress Dysfunctions. Treatments for emotional and physical distress, such as anxiety, depression, anger, insomnia, mood disorders, substance and behavioral addictions, eating disorders, sexual disorders, gastrointestinal disorders, attention-deficit disorders, and distressing pain, have generally involved the administration of anti-anxiety and anti-depressant medications, opioid and non-opioid analgesics, and stimulants. These treatments have been limited and often ineffective as well as the cause of serious, but avoidable, side effects. Conventional treatment lacks the knowledge and teaching described and developed through this invention, especially regarding the critical role of the protracted excitatory receptor mode and diminished neurotransmitter levels in endogenous opioid and related systems, characteristic of most Distress Dysfunction disorders, conditions, and symptoms.
Prior teachings and practices frequently resorted to supplementing endogenous neurotransmitters with exogenous substitutes, such as the extensive use of narcotic opioid drugs. Unfortunately, this approach has revealed very serious and dangerous consequences including the development of hyperalgesia, tolerance, dependence, and addiction, which, according to our discoveries, result directly from the homeostatic compensatory response of the endogenous opioid system that includes protracted suppression of endogenous neurotransmitters, such as endorphins, as well as protracted fixation of the receptors in the excitatory mode. In other words, use of exogenous opioids literally produces a protracted imbalance in the endogenous opioid system, exacerbating protracted distress symptoms, increasing the reliance on these drugs, and setting the stage for drug dependence and addiction. A similar problem exists in current opioid addiction treatment, in which “treatment” is simply administering more exogenous opioid drugs, such as buprenorphine, which continues the drug dependency and impairment of the homeostatic functioning of the stress-related neurotransmitter systems.
There is also growing evidence that many other pain and distress relieving agents, including NSAIDs, such as celecoxib and acetaminophen, function through the endogenous opioid system, as shown in cross-tolerance studies. In fact, there is evidence that celecoxib reduces pain, at least in part, by triggering the release of endogenous opioids. Given our discoveries regarding the impact of increasing endorphins when opioid receptors are in a distress, or protracted excitatory state, it is likely that many of the noxious side effects of NSAIDs, such as celecoxib, including tolerance and gastrointestinal symptoms, occur due to the triggering of protracted opioid excitatory signaling, similar to the impact of exogenous opioid drugs. Furthermore, the pain relieving effects, as shown in induced pain and clinical trials, are rather weak with non-opioid analgesics, and not sufficient for moderate-to-severe pain. Therefore, conventional treatment for emotional and physical distress is limited, with the more potent pharmaceuticals causing very dangerous and, at times, fatal consequences.
Clearly, neurotransmitter replacements, such as exogenous opioid and non-opioid analgesics, have had an important role in the management of physical and emotional distress, especially pain, despite their serious problems. However, using the discoveries underlying this invention, fortunately they can now be used as a last resort, in relatively small doses, in our novel formulations that have been developed to minimize the need for, and the iatrogenic impact of agents that compete with, and interfere with, healthy functioning of the stress response neurotransmitter systems.
An alternative approach to the treatment of emotional and physical distress has been the administration of agents that may increase the production, release, and functioning of neurotransmitters in the stress response system, rather than attempt to replace them with exogenous substitutes. For instance, the popular use of Selective Serotonin Reuptake Inhibitor (SSRI) and Selective Norepinephrine Reuptake Inhibitor (SNRI) medications, which increase the level of serotonin and norepinephrine, has shown partial effectiveness, with estimates that they generally may reduce distress symptoms of depression by about 10%. The variability of effectiveness is also striking, with many individuals having no benefit, or even an exacerbation of symptoms, using SSRI and SNRI medications. The problem, discovered by this invention, is that this popular treatment does not consider the important homeostatic interrelationship among the serontonergic and opioidergic and related neurotransmitter systems and the critical role of protracted excitatory opioid receptor signaling in reducing the therapeutic benefits from SSRIs, SNRIs, and other neurotransmitter enhancing agents. Cross-tolerance studies of exogenous serotonin and opioid agents demonstrate this underlying problem. There is evidence to suggest that tolerance and withdrawal effects often develop with the use of various anti-anxiety and anti-depressant medications, producing imbalances in these systems, ironically leading to increased protracted distress over time. Until this invention, there was no understanding of nor solution for, this problem with these medications.
A similar problem exists in the growing field of supplements used to reduce emotional and physical distress. This approach attempts to stimulate the production and release of stress-related neurotransmitters to enhance healthy neurotransmitter functioning. Most of this field focuses on administering forms of amino acids, vitamins and minerals, which target the production and release of specific neurotransmitters. For instance, tryptophan and 5HTP are often used to trigger the release of serotonin in an attempt to reduce distress and increase a sense of well-being. Similarly, dl-phenylalanine (DLPA) has been used to increase the release and maintenance of endorphins. This may have modest effectiveness when the receptors are in healthy homeostatic balance. Unfortunately, these agents provide either minimal effectiveness, or paradoxically, an increase in distress when individuals who suffer from Distress Dysfunction symptoms, caused by protracted opioid receptor excitatory signaling, use them. This understanding explains the limited and highly variable effectiveness of simply administering these supplements without the use of a Receptor Switcher, as discovered and defined by this invention. In fact, ironically, clinical experience has revealed that the more distress an individual experienced chronically, the more the administration of amino acid supplements, such as DLPA, produced increased, rather than reduced, distress. Until this invention, however, there was no explanation or solution to this variable and, at times, iatrogenic effects of neurotransmitter enhancing agents.
Another approach to the reduction of distress, especially used in the field of drug and alcohol dependence, has been to administer a large dose of neurotransmitter antagonists, such as naltrexone, in an attempt to reduce cravings and prevent the effects of these abused substances on the neurotransmitter system. While these high dose opioid antagonists effectively block protracted excitatory signaling, they also block inhibitory signaling as well, leading to reduced pleasure and pain control. This treatment has very poor compliance because individuals typically become anhedonic, leading to limited motivation to continue taking the antagonist. Recently approved medications remove the daily choice from this method of treatment by administering long-term dosing of these drugs. Unfortunately, this approach to treating distress dysfunction is counterproductive because it blocks the release of endogenous opioids and related neurotransmitters, thereby dramatically impairing homeostatic balance in these systems and causing a continuous state of anhedonia and hyperalgesia, which, in turn, mitigates against long-term success and compliance. In certain ways, it could be considered a more finely tuned chemical lobotomy.
Similarly, investigators at Orexigen Therapeutics have taught the combination of certain opioid antagonists, such as naltrexone, with certain Synergistic Enhancers, specifically SSRIs. Unfortunately, without an understanding of Receptor Switchers, they use conventional doses of naltrexone, which, according to the discoveries of this invention, will have reduced, if any, initial benefits as well as long-term iatrogenic effects since higher doses of opioid antagonists block all opioid receptor signaling.
A similar problem exists with prior teachings that suggested high dose naltrexone in combination with Nerve Growth Factor (NGF) for the treatment of HIV-induced and diabetic neuropathy. NGF can be an effective treatment for various conditions, including HIV-induced and diabetic neuropathy, but it is well known that NGF produces hyperalgesia and pain, reflecting protracted excitatory opioid receptor signaling. Although Crain et al. (U.S. Pat. No. 5,585,348) recognized the potential of a co-treatment approach for diabetic neuropathy to reduce the painful side-effects of NGF, they taught the use of oral naltrexone in the dose range of 25-50 milligrams. The present invention indicates that this is not only ineffective, but will produce serious noxious side effects since naltrexone at this dose literally blocks all opioid receptor activity, including inhibitory signaling. Therefore, as recommended by this prior teaching, the net effect of combining NGF with high dose naltrexone is an increase in Distress Dysfunction, including pain and hyperalgesia, over time.
A group of investigators at Pfizer has taken an even more problematic route. Noting that exogenous nerve growth factor (NGF) produces a serious side effect of pain, they postulated that treatment that reduces endogenous NGF levels in the body could be an effective treatment for chronic pain (U.S. Pat. No. 7,655,231 for “Methods for treating pain by administering a nerve growth factor antagonist and an NSAID”). While early results weakly support this theory, this approach is likely to lead to very serious long-term consequences since endogenous NGF is known to have extremely important roles in a wide variety of physiological processes. Therefore, a fundamentally different methodology is needed to reduce the noxious hyperalgesic effects of exogenous as well as endogenous NGF. The use of Receptor Switchers, as discovered and defined by this patent, provides a safe and effective solution to this problem.
Dr. Stanley Crain discovered the existence and function of agents that block excitatory opioid receptor signaling during his pioneering electrophysiological nervous tissue culture studies. His research led to the discovery that endogenous opioid receptors are bimodal and have two signaling modes—inhibitory and excitatory. When the receptor is in the inhibitory mode, endogenous opioids, such as endorphins, trigger inhibitory signaling, leading to immediate reduction of distressful pain signals. However, when the receptor is in the excitatory mode, endorphins trigger excitatory signaling, sending out distressing alert signals, often experienced as pain. If the neurotransmitter system is in homeostatic balance, the system is very efficient and effective, switching back and forth between excitatory (pain) and inhibitory (relief) signaling. However, Dr. Crain discovered that when exogenous opioid agents are administered, the system adapts rather quickly, leading to protracted excitatory signaling. In subsequent studies, Dr. Crain discovered that ultra-low-dose opioid antagonists, such as ultra-low-dose naltrexone (ULDN), reduced and/or eliminated protracted excitatory signaling. Dr. Crain later discovered that GM1 ganglioside attenuators, such as oseltamivir, also selectively block excitatory opioid receptor signaling.
Dr. Crain used these discoveries to develop improved approaches for the treatment of nociceptive pain and opioid drug addiction. He developed a method to reduce many of the noxious side effects of exogenous opioid drugs, such as tolerance and dependence, using co-treatment formulations that added specific agents, such as ULDN or oseltamivir, when administering opioid drugs (U.S. Pat. No. 7,026,329 for “Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bimodally-acting opioid agonists”; and WO 2010/0015147 for “Methods for increasing analgesic potency and attenuating adverse excitatory effects of bimodally-acting opioid agonists by inhibiting GM1-ganglioside”).
Dr. Crain also discovered that by combining agents, such as rolipram and monosodium glutamate (MSG), that normally increase hyperalgesia and pain, presumably by triggering excitatory opioid receptor signaling, with agents such as ULDN or oseltamivir, the hyperalgesic effects could be blocked and reversed, producing analgesia. These preclinical studies led Dr. Crain to propose novel non-opioid formulations for the treatment of nociceptive pain and opioid addiction (WO 2010/0203084 for “Method for treating pain or opioid dependence using a specific type of non-opioid agent in combination with a selective excitatory-opioid-receptor inactivator”).
While Dr. Stanley Crain's preclinical studies revealed the importance of agents that selectively block excitatory opioid receptor signaling, his research was exclusively focused on nociceptive pain and the endogenous opioid system and not on the emotional and physical distress syndromes, which are the focus of this invention, and the critical interconnected role of other stress-related neurotransmitter systems, such as the serotonin, dopamine, glutamate, epinephrine, and norepinephrine systems. Dr. Crain's combination of Receptor Switchers, such as ultra-low-dose-naltrexone, with either Exogenous Opioids or Endorphin Enhancers, such as rolipram, was limited to nociceptive pain and opioid withdrawal. Dr. Crain neither addressed nor articulated any principles that predicted or contemplated the role of these formulations in the treatment of the comprehensive set of disorders, conditions, and symptoms that are manifested by Distress Dysfunction, as defined in this application, such as dysfunctional worries and anxieties, anger and irritability, despair and depression, sexual and sleep impairments, cravings for alcohol and food, or hypersensitivity or exaggerated responsitivity to perceived pain and stress.
Regarding one Distress Dysfunction disorder that Dr. Crain's team did address, Irritable Bowel Syndrome (U.S. Pat. No. 6,395,705), they taught the use of low-dose naltrexone alone, which, without agents that simultaneously enhance endorphin levels (Endorphin Enhancers), has been shown to be ineffective for symptom reduction over time. Similarly, teachings from Dr. Stanley Crain and Dr. Paolo Mannelli have suggested the use of ultra-low-dose and very-low-dose naltrexone alone to facilitate withdrawal from chronic opioid dependence. However, they neglected the critical principle, discovered by this invention, that co-treatment with at least an Endorphin Enhancer, such as roflumilast or ginkgo biloba, is critical to enhance depleted endorphins and other stress-related neurotransmitters underlying substance dependence. Furthermore, this invention uniquely teaches the synergistic treatment benefits that are seen when adding Synergistic Enhancers, such as specific amino acids, to these co-treatment formulations.
One group at Pharmorx has recently taught the use of ultra-low-dose opioid antagonists for “preventing or reversing loss of therapeutic effect, where loss is associated with the repeated administration” of dopamine-related agents (WO 2010/0168119). However, their discovery only relates to the loss of effects of dopamine-related agents, with no teaching regarding the extensive therapeutic benefits, well beyond tolerance, for a wide variety of Distress Dysfunction disorders, of using ultra-low-dose and very-low-dose opioid antagonists, and a variety of other Receptor Switchers, in combination with the Endorphin Enhancers, such as the cAMP PDE inhibitors and excitatory amino acids, and the Synergistic Enhancers, such as the serotonin reuptake inhibitors, norepinephrine reuptake inhibitors, and the analgesics, discovered by this invention. Furthermore, these investigators only used ultra-low-dose opioid antagonists (up to a maximum of “1.5 μg/kg”), which ignores the limited oral bioavailabilty of these agents, such as naltrexone. Our findings show that relatively higher doses of agents, such as naltrexone in the 125-150 microgram range, are more likely to have reliable and consistent benefits across people and conditions. Furthermore, their teaching ignores the remarkable therapeutic benefits of the other Receptor Switchers, such as neuraminidase inhibitors, discovered by this invention.
With regard to the treatment of nociceptive pain and opioid dependence, although Dr. Crain conducted nervous tissue culture and animal models, he neither studied nor identified the formulations and agents that would, in fact, be appropriate, safe and effective agents for human consumption and clinical application. (Indeed rolipram, the only agent that Dr. Crain twice referred to in his patent as part of a “preferred embodiment” has been shown to exhibit noxious gastrointestinal effects, thereby making it unsuitable for human clinical application in humans.) Furthermore, Dr. Crain's teachings are silent regarding the critical importance of using Exogenous Opioids only in combination with both Receptor Switchers and Endorphin Enhancers, which serves to minimize the need and dose of Exogenous Opioids. Moreover there has been no teaching regarding the therapeutic benefits of adding specific Synergistic Enhancers, such as SSRI, NSAID, and amino acids, to these endorphinergic formulations of Receptor Switchers and Endorphin Enhancers, for nociceptive pain. Therefore, what is clearly needed is a way to block the noxious, hyperalgesic protracted excitatory signaling of opioid and related neurotransmitter receptors, without inhibiting the de-stressing pain-reducing inhibitory signaling.
A group of investigators at Avigen found evidence that ibudilast, a cAMP PDE inhibitor drug similar to rolipram, but more tolerable for human consumption, can be used for the treatment of pain and various addictions, though they attribute the benefits to glial cell mechanism and not to its cAMP PDE inhibition functions (WO 2006/0160843 and WO 2008/0181876). However, these investigators assert that the effectiveness of ibudilast for these disorders is based on its administration as a stand-alone medication, or in combination with Exogenous Opioids. As a result, they suggest no teachings regarding the critical need for the co-administration of any agent to reduce protracted excitatory opioid receptor signaling, such as a ULDN, with ibudilast for the most effective treatment of pain and addiction. Not only is this approach less effective, but also potentially iatrogenic since the administration of ibudilast and other PDE-inhibitors, as well as Exogenous Opioids without a Receptor Switcher, such as ULDN or VLDN, is likely to leave the receptors in the endogenous opioid system in a protracted excitatory state, making it much less effective for treating Distress Dysfunction and might even exacerbate emotional and physical distress, thereby exacerbating Distress Dysfunctions.
Additional examples of prior art directed to administering opioid antagonists and the treatment of pain, IBS, and other Distress Dysfunctions include US Patent Publication No. 20020198227 for “Method for curbing dietary craving” (describing administration of low dose naltrexone); US Patent Publication No. 20030191147 for “Opioid antagonist compositions and dosage forms”; US Patent Publication No. 20030211157 for “Semi-sol delivery blend for water soluble molecules”; US Patent Publication No. 20040072864 for “Method and composition for treatment of irritable bowel disease”; US Patent Publication No. 20060009478 for “Methods for the treatment of back pain” (does not describe the use of ultra low does naltrexone in combination with a non-opioid analgesic); US Patent Publication No. 20060069086 for “Methods for regulating neurotransmitter systems by inducing counteradaptations” (does not describe ultra low does naltrexone or co-treatment); US Patent Publication No. 20070099947 for “Methods and compositions for the treatment of brain reward system disorders by combination therapy” (does not describe ultra low does naltrexone); US Patent Publication No. 20080045610 for “Methods for regulating neurotransmitter systems by inducing counteradaptations”; US Patent Publication No. 20080207601 for “Methods of and Compositions For the Prevention of Anxiety, Substance Abuse, and Dependence” (cotreatment agents are steroids); US Patent Publication No. 20080255097 for “Methods for the Treatment of Substance Abuse and Dependence”; US Patent Publication No. 20100144645 for “Compositions and Methods for Enhancing Analgesic Potency of Covalently Bound-Compounds . . . ”; US Patent Publication No. 20100168119 for “Compositions and Methods for Minimizing or Reducing Agonist-Induced Desensitization”; U.S. Pat. Nos. 6,458,795, 6,664,270 and 6,818,656, all for “Method and composition for treatment of irritable bowel disease”; U.S. Pat. No. 6,972,291 for “Method for reducing food intake” (describing administration of low does (not ultra low does) naltrexone); WO 2007/056300 for “Methods and Compositions for the Treatment of Brain Reward System Disorders by Combination Therapy”; WO 2000/067739 for “Opioid Antagonists Containing Compositions for Enhancing Analgesic Potency of Tramadol and Attenuating its Adverse Side Effects”; WO 2006/034343 for “Methods for regulating neurotransmitter systems by inducing counteradaptations”; WO 2006/110557 for “Methods for the Treatment of Substance Abuse and Dependence”; WO 2007/100775 for “Methods for Regulating Neurotransmitter Systems by Inducing Counteradaptations”; WO 2007/120864 for “Compositions and Methods for Enhancing Analgesic Potency of Covalently Bound Compounds . . . ”; WO 2008/094571 for “Methods for Treating Acute and Subchronic Pain”; WO 2009/017625 for “Treatment of Depression, Psychosis, and Anxiety”; and WO 2010/053835 for “Compositions and Methods for Minimizing or Reversing Agonist-Induced Desensitization.” However, there is no prior art that teaches the critical importance of understanding the role of protracted excitatory opioid (and related) receptor signaling, together with diminished opioid (and related) neurotransmitters, in Distress Dysfunctions, and its clinical implication for the use of Receptor Balancers combined with Endorphin Enhancers and/or Synergistic Enhancers and/or Exogenous Opioids for safe and effective treatment.
There is a need in the art for improved methods and compositions for treating Distress Dysfunctions. The present invention satisfies these needs.